Microglial Modulation in Neurodegenerative Diseases

Microglia, the resident immune cells of the central nervous system, play a dual role in neurodegenerative diseases by both propagating and restraining pathology. In Alzheimer’s disease, these cells influence the initiation, compaction and clearance of amyloid-β plaques, while in tauopathies and other disorders they can either exacerbate protein aggregation or promote repair. Advances in genetic and pharmacological approaches have revealed stage-specific functions of microglia, from seeding pathological deposits to limiting neuritic damage at later stages. Strategies that selectively deplete, rejuvenate or reprogramme microglial phenotypes offer promising avenues for therapy. Nanoparticle-mediated delivery of siRNA or small-molecule inhibitors, for example, can restore homeostatic functions and enhance phagocytic clearance of toxic aggregates, thereby improving cognition and synaptic integrity. Ongoing work aims to refine interventions that balance neuroprotective and inflammatory responses, with the ultimate goal of translating microglial modulation into disease-modifying treatments across a spectrum of dementia and movement disorders.

Research from Nature Portfolio

Recent studies have delineated a nuanced, stage-dependent role for microglia in Alzheimer’s pathology. One investigation demonstrated that early depletion of microglia before amyloid-β deposition markedly reduces plaque initiation and neuritic dystrophy, while later removal impairs plaque compaction and aggravates neuronal damage. Transplantation of human microglia confirmed their essential role in plaque seeding, and genetic variants such as TREM2R47H were shown to worsen pathology by altering microglial activation states. Another foundational report employed a brain-penetrant colony-stimulating factor 1 receptor (CSF1R) inhibitor to achieve sustained microglial elimination in a transgenic model. The absence of microglia prevented parenchymal plaque formation entirely, redirected amyloid to vascular compartments and reversed disease-associated gene expression, highlighting the critical involvement of microglia in both plaque genesis and associated neuroinflammation.

Microglial Modulation in Neurodegenerative Diseases publication trend

The graph below shows the total number of articles in microglial modulation in neurodegenerative diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Microglia: The primary innate immune cells of the central nervous system responsible for surveying and maintaining brain homeostasis.

CSF1R: Colony-stimulating factor 1 receptor, essential for microglial survival and proliferation, often targeted to modulate microglial populations.

Phagocytosis: The process by which microglia internalise and degrade cellular debris or protein aggregates.

Amyloid-β plaque: Extracellular deposits of aggregated Aβ peptides that characterise Alzheimer’s disease pathology.

Disease-associated microglia (DAM): A microglial activation state defined by a distinct transcriptional signature linked to neurodegenerative environments.

References

1. Rejuvenating aged microglia by p16ink4a-siRNA-loaded nanoparticles increases amyloid-β clearance in animal models of Alzheimer’s disease. Molecular Neurodegeneration (2024).
2. Homeostatic microglia initially seed and activated microglia later reshape amyloid plaques in Alzheimer’s Disease. Nature Communications (2024).
3. Single-cell spatial transcriptomics reveals distinct patterns of dysregulation in non-neuronal and neuronal cells induced by the Trem2R47H Alzheimer’s risk gene mutation. Molecular Psychiatry (2024).
4. Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model. Nature Communications (2019).
5. CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice. Brain (2019).